The c-Myc bHLH-ZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism and differentiation at the cellular, tissue or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc?s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a non-linear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. Current investigations are exploring the molecular mechanisms exploited by MYC to augment gene expression and to demonstrate how small changes in MYC levels or short pulses of MYC activity may modify the growth of normal and neoplastic cells. The theory that MYC is an amplifier was derived from genome-wide studies of MYC and RNA polymerase binding to chromatin in vivo and RNA expression. We are now testing this theory with an orthogonal set of methods and experiments based on transfections and synthetic biology that thus far fully confirm the predictions of the amplifier model.